The present invention relates to difluoromethylene aromatic ethers containing a pendant amino acid side chain and to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in mammals, including humans. These compounds exhibit activity as inhibitors of the glycine type-1 transporter.
Pharmacological treatment for schizophrenia has traditionally involved blockade of the dopamine system, which is thought to be responsible for its positive symptoms. Such treatment, however, ignores the negative and cognitive aspects of the disease. Another neurotransmitter system believed to play a role in schizophrenia is the glutamate system, the major excitatory transmitter system in the brain. This hypothesis is based on the observation that blockade of the glutamate system by compounds such as PCP (xe2x80x9cangel dustxe2x80x9d) can replicate many of the symptoms of schizophrenia, including its positive, negative, and cognitive aspects. If schizophrenia involves a deficit of glutamatergic transmission, augmentation of the glutamate system, and specifically the NMDA receptor, may be beneficial. While glutamate is the principle agonist at NMDA receptors, glycine is required as a co-agonist to set the xe2x80x9ctonexe2x80x9d of the receptor for its response to glutamate. Enhancing this xe2x80x9ctonexe2x80x9d by increasing the effect of glycine would augment NMDA neurotransmission, and provide potential benefit in the treatment of schizophrenia.
A specific mechanism for augmenting the glycinergic xe2x80x9ctonexe2x80x9d of the NMDA receptor was disclosed recently by Bergeron, et al. (Proc. Natl. Acad. Sci. USA, 95, 15730, (1998)). This group showed that a specific and potent inhibitor of the glycine type-1 transporter (GlyT1) responsible for removing glycine from the synapse at the NMDA receptor, termed NFPS (WO 97/45115), can enhance NMDA receptor function. For example, NFPS increased the post synaptic current driven by the NMDA receptor, an effect blocked by both a specific NMDA-site antagonist and a glycine-site antagonist. Even though glycine levels in the brain are high relative to the amount required to act as an NMDA receptor co-agonist, this work shows that GlyT1 removes glycine efficiently at the synapse, and that inhibition of GlyT1 can augment NMDA receptor function. The authors establish the feasibility of using a GlyT1 inhibitor as a treatment for schizophrenia through its augmentation of glutamatergic neurotransmission.
The present invention relates to a series of compounds of the formula: 
wherein ring A is phenyl, naphthyl, benzothienyl, benzofuranyl, or thienyl; or ring A is a monocyclic aryl or heteroaryl ring containing from zero to four heteroatoms and not containing any adjacent ring oxygen atoms; or ring A is a bicyclic aryl or heteroaryl ring containing from zero to five heteroatoms and not containing any adjacent ring oxygen atoms; and
X and Y are each, independently, (C1-C6) alkyl optionally substituted with from one to seven fluorine atoms; (C1-C6)alkoxy optionally substituted with from one to seven fluorine atoms, wherein the number of fluorine substituents on the foregoing (C1-C6) alkyl and (C1-C6) alkoxy groups cannot exceed the number of positions in such groups that are available for substitution; carboxy; carbo-(C1-C6)alkoxy; carboxamido; (C1-C6)alkyl-thio; sulfoxyl; sulfonyl; halo; nitro; cyano; amino; (C1-C6) alkylamino and di[(C1-C6) alkyl]amino;
and the pharmaceutically acceptable salts of such compounds.
In a preferred embodiment of this invention, ring A is selected from phenyl, naphthyl benzofuranyl, benzothienyl, indanyl, tetrahydronaphthyl, dihydrobenzofuranyl, and dihydrobenzothiophenyl. In another preferred embodiment of this invention, X is para-trifluoromethyl, para-methyl or para-chloro.
The present invention also relates to a compound having the formula: 
wherein Y is (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms; (C1-C6)alkoxy optionally substituted with from one to seven fluorine atoms, wherein the number of fluorine substituents on the foregoing (C1-C6)alkyl and (C1-C6) alkoxy groups can not exceed the number of positions in such groups that are available for substitution; carboxy; carbo-(C1-C6)alkoxy; carboxamido; (C1-C6)alkyl-thio; sulfoxyl; sulfonyl; halo; nitro; cyano; amino; (C1-C6) alkylamino and di{(C1-C6)alkyl}amino;
wherein Z1 and Z2 are independently selected from O, NH, N-(C1-C5 alkyl), and S; and n is an integer from 1 to about 3;
or a pharmaceutically acceptable salt thereof.
Specific compounds of the invention include:
({3-[3-(Difluoro-(phenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[3-(Difluoro-(4-methoxyphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[3-(Difluoro-(4-methylphenyl)methyl)phenoxyl]-3-phenylpropyl}methylamino)acetic acid;
({3-[3-(Difluoro-(4-chlorophenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[3-(Difluoro-(2,4-difluoroorophenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[3-(Difluoro-(benzo[b]furan-5-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(phenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-methoxyphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-methylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-chlorophenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(phenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid; ({3-[4-(Difluoro-(benzo[b]furan-5-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-(4-Fluoro)phenyl-3-[4-(difluoro-(benzo[b]furan-5-yl)methyl)phenoxy]propyl}methylamino)acetic acid;
({3-(2,4-Difluoro)phenyl-3-[4-(difluoro-(benzo[b]furan-5-yl)methyl)phenoxy]propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-methylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid; and
({3-[4-(Difluoro-(4-chlorophenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid.
Other embodiments of the invention include:
({3-(4-Fluorophenyl)-3-[4-(difluoro-(5,6,7,8-tetrahydronaphthalen-1-yl)methyl)phenoxy]propyl}-methylamino)acetic acid;
({3-[4-(Difluoro-(2,4-dimethylphenyl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
({3-(4-Fluorophenyl)-3-[4-(difluoro-(2,4,6-trimethylphenyl)methyl)phenoxy]propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(5,6,7,8-tetrahydronaphthalen-1-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2,4-dimethylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-cyclohexylphenyl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-cyclopentylphenyl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-cyclohexylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-cyclopentylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2,3-dihydrobenzo[1,4]dioxin-5-yl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}-methylamino)acetic acid;
({3-[4-(Difluoro-(2,3-dihydrobenzo[1,4]dioxin-5-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2,3-dihydrobenzofuran-7-yl)methyl)phenoxy]-3-(4-fluorophenyl)-propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2,3-Dihydrobenzofuran-7-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(benzofuran-4-yl)methyl)phenoxy]-3-(4-fluorophenyl)-propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2,3-dihydrobenzofuran-4-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2,3-dihydrobenzofuran-4-yl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(3,5-bis(trifluoromethyl)phenyl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
({3-(4-Fluorophenyl)-3-[4-(difluoro-(4-(trifluoromethoxy)phenyl)methyl)phenoxy]propyl}methylamino)acetic acid;
(Methyl-{3-phenyl-3-[4-(difluoro-(4-trifluoromethoxyphenyl)methyl)phenoxy]propyl}amino)acetic acid;
({3-[4-(Difluoro-(benzo[1,3]dioxol-5-yl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(benzo[1,3]dioxol-5-yl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(3-methoxyphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-(4-Fluorophenyl)-3-[4-(difluoro-(3-methoxyphenyl)methyl)phenoxy]propyl}methylamino)acetic acid;
(Methyl-{3-phenyl-3-[4-(difluoro-(3-trifluoromethoxyphenyl)methyl)phenoxy]propyl}amino)acetic acid;
({3-(4-Fluorophenyl)-3-[4-(difluoro-(3-trifluoromethoxyphenyl)methyl)phenoxy]propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(2-methoxyphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-(4-Fluorophenyl)-3-[4-(difluoro-(2-methoxyphenyl)methyl)phenoxy]propyl}methylamino)acetic acid;
({3-[4-(Difluoro-(3,4-dimethoxyphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(3,4-dimethoxyphenyl)methyl)phenoxy]-3-(4-fluorophenyl)propyl}methylamino)acetic acid;
(Methyl-{3-(4-trifluoromethyl)phenyl-3-[4-(difluoro-(3-methoxyphenyl)methyl)-phenoxy]propyl}amino)acetic acid;
(Methyl-{3-phenyl-3-[4-(difluoro-(3-trifluoromethylphenyl)methyl)phenoxy]propyl}amino)acetic acid;
(Methyl-{3-phenyl-3-[4-(difluoro-(p-tolyl)methyl)phenoxy]propyl}amino)acetic acid;
(Methyl-3-{[4-(difluoro-(naphthalen-2-yl)methyl)phenoxy]-3-phenylpropyl}amino)acetic acid;
({3-[4-(Difluoro-(4-isopropylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
({3-[4-(Difluoro-(4-t-butylphenyl)methyl)phenoxy]-3-phenylpropyl}methylamino)acetic acid;
(Methyl-{3-phenyl-3-[4-(difluoro-(4-trifluoromethylphenyl)methyl)phenoxy]propyl}amino)acetic;
(Methyl-{3-phenyl-3-[4-(difluoro-(5,6,7,8-tetrahydronaphthalen-2-yl)methyl)phenoxy]propyl}amino)acetic acid;
(Methyl-{3-[4-(difluoro-(benzo[b]thien-5-yl)methyl)phenoxy]-3-phenylpropyl}amino)acetic acid; and
(Methyl-{3-(4-fluorophenyl)-{3-[4-(difluoro-(benzo[b]thien-5-yl)methyl)phenoxy]propyl}amino)acetic acid.
This invention also relates to a method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette""s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson""s disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia, and senile dementia of the Alzheimer""s type) and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such condition or disorder.
This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette""s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson""s disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer""s type) and memory disorders in a mammal, including a human, comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating such disorder or condition.
This invention also relates to a method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette""s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson""s disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer""s type) and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment a glycine transport-inhibiting amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette""s syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson""s disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer""s type) and memory disorders in a mammal, including a human, comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, in a glycine transport-inhibiting amount.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. Examples of xe2x80x9calkylxe2x80x9d groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
The term xe2x80x9chaloxe2x80x9d, as used herein, means chloro, fluoro, iodo or bromo.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, means xe2x80x9calkyl-O-xe2x80x9d, wherein xe2x80x9calkylxe2x80x9d is defined as above.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The compounds of formula I may have optical centers and therefore may occur in different enantiomeric configurations. Formula I, as depicted above, includes all enantiomers, diastereomers, and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.
The present invention also includes isotopically labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium and 14C isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Scheme and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.